Open Biology最新文献_第6页

A myzozoan-specific protein is an essential membrane-anchoring component of the succinate dehydrogenase complex in Toxoplasma parasites. 弓形虫体内的琥珀酸脱氢酶复合物中，有一种虫体特异性蛋白是必不可少的膜锚定成分。

IF 4.5 3区生物学

Open Biology Pub Date : 2024-06-01 Epub Date: 2024-06-04 DOI: 10.1098/rsob.230463

Soraya M Zwahlen, Jenni A Hayward, Capella S Maguire, Alex R Qin, Giel G van Dooren

{"title":"A myzozoan-specific protein is an essential membrane-anchoring component of the succinate dehydrogenase complex in Toxoplasma parasites.","authors":"Soraya M Zwahlen, Jenni A Hayward, Capella S Maguire, Alex R Qin, Giel G van Dooren","doi":"10.1098/rsob.230463","DOIUrl":"10.1098/rsob.230463","url":null,"abstract":"Succinate dehydrogenase (SDH) is a protein complex that functions in the tricarboxylic acid cycle and the electron transport chain of mitochondria. In most eukaryotes, SDH is highly conserved and comprises the following four subunits: SdhA and SdhB form the catalytic core of the complex, while SdhC and SdhD anchor the complex in the membrane. Toxoplasma gondii is an apicomplexan parasite that infects one-third of humans worldwide. The genome of T. gondii encodes homologues of the catalytic subunits SdhA and SdhB, although the physiological role of the SDH complex in the parasite and the identity of the membrane-anchoring subunits are poorly understood. Here, we show that the SDH complex contributes to optimal proliferation and O2 consumption in the disease-causing tachyzoite stage of the T. gondii life cycle. We characterize a small membrane-bound subunit of the SDH complex called mitochondrial protein ookinete developmental defect (MPODD), which is conserved among myzozoans, a phylogenetic grouping that incorporates apicomplexan parasites and their closest free-living relatives. We demonstrate that TgMPODD is essential for SDH activity and plays a key role in attaching the TgSdhA and TgSdhB proteins to the membrane anchor of the complex. Our findings highlight a unique and important feature of mitochondrial energy metabolism in apicomplexan parasites and their relatives.","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 6","pages":"230463"},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Decoding frontotemporal and cell-type-specific vulnerabilities to neuropsychiatric disorders and psychoactive drugs. 解码额颞叶和细胞类型对神经精神疾病和精神活性药物的特异脆弱性。

IF 4.5 3区生物学

Open Biology Pub Date : 2024-06-01 Epub Date: 2024-06-12 DOI: 10.1098/rsob.240063

Jiatong Ji, Honglu Chao, Huimei Chen, Jun Liao, Wenqian Shi, Yangfan Ye, Tian Wang, Yongping You, Ning Liu, Jing Ji, Enrico Petretto

{"title":"Decoding frontotemporal and cell-type-specific vulnerabilities to neuropsychiatric disorders and psychoactive drugs.","authors":"Jiatong Ji, Honglu Chao, Huimei Chen, Jun Liao, Wenqian Shi, Yangfan Ye, Tian Wang, Yongping You, Ning Liu, Jing Ji, Enrico Petretto","doi":"10.1098/rsob.240063","DOIUrl":"10.1098/rsob.240063","url":null,"abstract":"Frontotemporal lobe abnormalities are linked to neuropsychiatric disorders and cognition, but the role of cellular heterogeneity between temporal lobe (TL) and frontal lobe (FL) in the vulnerability to genetic risk factors remains to be elucidated. We integrated single-nucleus transcriptome analysis in 'fresh' human FL and TL with genetic susceptibility, gene dysregulation in neuropsychiatric disease and psychoactive drug response data. We show how intrinsic differences between TL and FL contribute to the vulnerability of specific cell types to both genetic risk factors and psychoactive drugs. Neuronal populations, specifically PVALB neurons, were most highly vulnerable to genetic risk factors for psychiatric disease. These psychiatric disease-associated genes were mostly upregulated in the TL, and dysregulated in the brain of patients with obsessive-compulsive disorder, bipolar disorder and schizophrenia. Among these genes, GRIN2A and SLC12A5, implicated in schizophrenia and bipolar disorder, were significantly upregulated in TL PVALB neurons and in psychiatric disease patients' brain. PVALB neurons from the TL were twofold more vulnerable to psychoactive drugs than to genetic risk factors, showing the influence and specificity of frontotemporal lobe differences on cell vulnerabilities. These studies provide a cell type resolved map of the impact of brain regional differences on cell type vulnerabilities in neuropsychiatric disorders.","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 6","pages":"240063"},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of the modulatory Ca²⁺-binding sites of acid-sensing ion channel 1a. 鉴定酸感应离子通道 1a 的 Ca2+ 结合调节位点

IF 4.5 3区生物学

Open Biology Pub Date : 2024-06-01 Epub Date: 2024-06-19 DOI: 10.1098/rsob.240028

Ophélie Molton, Olivier Bignucolo, Stephan Kellenberger

{"title":"Identification of the modulatory Ca2+-binding sites of acid-sensing ion channel 1a.","authors":"Ophélie Molton, Olivier Bignucolo, Stephan Kellenberger","doi":"10.1098/rsob.240028","DOIUrl":"10.1098/rsob.240028","url":null,"abstract":"Acid-sensing ion channels (ASICs) are neuronal Na+-permeable ion channels activated by extracellular acidification. ASICs are involved in learning, fear sensing, pain sensation and neurodegeneration. Increasing the extracellular Ca2+ concentration decreases the H+ sensitivity of ASIC1a, suggesting a competition for binding sites between H+ and Ca2+ ions. Here, we predicted candidate residues for Ca2+ binding on ASIC1a, based on available structural information and our molecular dynamics simulations. With functional measurements, we identified several residues in cavities previously associated with pH-dependent gating, whose mutation reduced the modulation by extracellular Ca2+ of the ASIC1a pH dependence of activation and desensitization. This occurred likely owing to a disruption of Ca2+ binding. Our results link one of the two predicted Ca2+-binding sites in each ASIC1a acidic pocket to the modulation of channel activation. Mg2+ regulates ASICs in a similar way as does Ca2+. We show that Mg2+ shares some of the binding sites with Ca2+. Finally, we provide evidence that some of the ASIC1a Ca2+-binding sites are functionally conserved in the splice variant ASIC1b. Our identification of divalent cation-binding sites in ASIC1a shows how Ca2+ affects ASIC1a gating, elucidating a regulatory mechanism present in many ion channels.","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 6","pages":"240028"},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141420297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Terminal regions of a protein are a hotspot for low complexity regions and selection. 蛋白质的末端区域是低复杂性区域和选择的热点。

IF 4.5 3区生物学

Open Biology Pub Date : 2024-06-01 Epub Date: 2024-06-12 DOI: 10.1098/rsob.230439

Lokdeep Teekas, Sandhya Sharma, Nagarjun Vijay

{"title":"Terminal regions of a protein are a hotspot for low complexity regions and selection.","authors":"Lokdeep Teekas, Sandhya Sharma, Nagarjun Vijay","doi":"10.1098/rsob.230439","DOIUrl":"10.1098/rsob.230439","url":null,"abstract":"Volatile low complexity regions (LCRs) are a novel source of adaptive variation, functional diversification and evolutionary novelty. An interplay of selection and mutation governs the composition and length of low complexity regions. High %GC and mutations provide length variability because of mechanisms like replication slippage. Owing to the complex dynamics between selection and mutation, we need a better understanding of their coexistence. Our findings underscore that positively selected sites (PSS) and low complexity regions prefer the terminal regions of genes, co-occurring in most Tetrapoda clades. We observed that positively selected sites within a gene have position-specific roles. Central-positively selected site genes primarily participate in defence responses, whereas terminal-positively selected site genes exhibit non-specific functions. Low complexity region-containing genes in the Tetrapoda clade exhibit a significantly higher %GC and lower ω (dN/dS: non-synonymous substitution rate/synonymous substitution rate) compared with genes without low complexity regions. This lower ω implies that despite providing rapid functional diversity, low complexity region-containing genes are subjected to intense purifying selection. Furthermore, we observe that low complexity regions consistently display ubiquitous prevalence at lower purity levels, but exhibit a preference for specific positions within a gene as the purity of the low complexity region stretch increases, implying a composition-dependent evolutionary role. Our findings collectively contribute to the understanding of how genetic diversity and adaptation are shaped by the interplay of selection and low complexity regions in the Tetrapoda clade.","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 6","pages":"230439"},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The cytosolic form of dual localized BolA family protein Bol3 is important for adaptation to iron starvation in Aspergillus fumigatus. 双重定位的 BolA 家族蛋白 Bol3 的胞浆形式对于曲霉适应铁饥饿非常重要。

IF 4.5 3区生物学

Open Biology Pub Date : 2024-06-01 Epub Date: 2024-06-26 DOI: 10.1098/rsob.240033

Simon Oberegger, Matthias Misslinger, Klaus Faserl, Bettina Sarg, Hesso Farhan, Hubertus Haas

{"title":"The cytosolic form of dual localized BolA family protein Bol3 is important for adaptation to iron starvation in Aspergillus fumigatus.","authors":"Simon Oberegger, Matthias Misslinger, Klaus Faserl, Bettina Sarg, Hesso Farhan, Hubertus Haas","doi":"10.1098/rsob.240033","DOIUrl":"10.1098/rsob.240033","url":null,"abstract":"Aspergillus fumigatus is the predominant mould pathogen for humans. Adaption to host-imposed iron limitation has previously been demonstrated to be essential for its virulence. [2Fe-2S] clusters are crucial as cofactors of several metabolic pathways and mediate cytosolic/nuclear iron sensing in fungi including A. fumigatus. [2Fe-2S] cluster trafficking has been shown to involve BolA family proteins in both mitochondria and the cytosol/nucleus. Interestingly, both A. fumigatus homologues, termed Bol1 and Bol3, possess mitochondrial targeting sequences, suggesting the lack of cytosolic/nuclear versions. Here, we show by the combination of mutational, proteomic and fluorescence microscopic analyses that expression of the Bol3 encoding gene leads to dual localization of gene products to mitochondria and the cytosol/nucleus via alternative translation initiation downstream of the mitochondrial targeting sequence, which appears to be highly conserved in various Aspergillus species. Lack of either mitochondrial Bol1 or Bol3 was phenotypically inconspicuous while lack of cytosolic/nuclear Bol3 impaired growth during iron limitation but not iron sensing which indicates a particular importance of [2Fe-2S] cluster trafficking during iron limitation. Remarkably, cytosolic/nuclear Bol3 differs from the mitochondrial version only by N-terminal acetylation, a finding that was only possible by mutational hypothesis testing.","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 6","pages":"240033"},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural and functional characterization of nanobodies that neutralize Omicron variants of SARS-CoV-2. 中和 SARS-CoV-2 Omicron 变体的纳米抗体的结构和功能特征。

IF 4.5 3区生物学

Open Biology Pub Date : 2024-06-01 Epub Date: 2024-06-04 DOI: 10.1098/rsob.230252

Katy Cornish, Jiandong Huo, Luke Jones, Parul Sharma, Joseph W Thrush, Sahar Abdelkarim, Anja Kipar, Siva Ramadurai, Miriam Weckener, Halina Mikolajek, Sai Liu, Imogen Buckle, Eleanor Bentley, Adam Kirby, Ximeng Han, Stephen M Laidlaw, Michelle Hill, Lauren Eyssen, Chelsea Norman, Audrey Le Bas, John Clarke, William James, James P Stewart, Miles Carroll, James H Naismith, Raymond J Owens

{"title":"Structural and functional characterization of nanobodies that neutralize Omicron variants of SARS-CoV-2.","authors":"Katy Cornish, Jiandong Huo, Luke Jones, Parul Sharma, Joseph W Thrush, Sahar Abdelkarim, Anja Kipar, Siva Ramadurai, Miriam Weckener, Halina Mikolajek, Sai Liu, Imogen Buckle, Eleanor Bentley, Adam Kirby, Ximeng Han, Stephen M Laidlaw, Michelle Hill, Lauren Eyssen, Chelsea Norman, Audrey Le Bas, John Clarke, William James, James P Stewart, Miles Carroll, James H Naismith, Raymond J Owens","doi":"10.1098/rsob.230252","DOIUrl":"10.1098/rsob.230252","url":null,"abstract":"The Omicron strains of SARS-CoV-2 pose a significant challenge to the development of effective antibody-based treatments as immune evasion has compromised most available immune therapeutics. Therefore, in the 'arms race' with the virus, there is a continuing need to identify new biologics for the prevention or treatment of SARS-CoV-2 infections. Here, we report the isolation of nanobodies that bind to the Omicron BA.1 spike protein by screening nanobody phage display libraries previously generated from llamas immunized with either the Wuhan or Beta spike proteins. The structure and binding properties of three of these nanobodies (A8, H6 and B5-5) have been characterized in detail providing insight into their binding epitopes on the Omicron spike protein. Trimeric versions of H6 and B5-5 neutralized the SARS-CoV-2 variant of concern BA.5 both in vitro and in the hamster model of COVID-19 following nasal administration. Thus, either alone or in combination could serve as starting points for the development of new anti-viral immunotherapeutics.","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 6","pages":"230252"},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Plasmodium LCCL domain-containing modular proteins have their origins in the ancestral alveolate. 疟原虫含 LCCL 结构域的模块蛋白起源于祖先的肺泡蛋白。

IF 4.5 3区生物学

Open Biology Pub Date : 2024-06-01 Epub Date: 2024-06-12 DOI: 10.1098/rsob.230451

Callum De Hoest-Thompson, Virginia Marugan-Hernandez, Johannes T Dessens

{"title":"Plasmodium LCCL domain-containing modular proteins have their origins in the ancestral alveolate.","authors":"Callum De Hoest-Thompson, Virginia Marugan-Hernandez, Johannes T Dessens","doi":"10.1098/rsob.230451","DOIUrl":"10.1098/rsob.230451","url":null,"abstract":"Plasmodium species encode a unique set of six modular proteins named LCCL lectin domain adhesive-like proteins (LAPs) that operate as a complex and that are essential for malaria parasite transmission from mosquito to vertebrate. LAPs possess complex architectures obtained through unique assemblies of conserved domains associated with lipid, protein and carbohydrate interactions, including the name-defining LCCL domain. Here, we assessed the prevalence of Plasmodium LAP orthologues across eukaryotic life. Our findings show orthologous conservation in all apicomplexans, with lineage-specific repertoires acquired through differential lap gene loss and duplication. Besides Apicomplexa, LAPs are found in their closest relatives: the photosynthetic chromerids, which encode the broadest repertoire including a novel membrane-bound LCCL protein. LAPs are notably absent from other alveolate lineages (dinoflagellates, perkinsids and ciliates), but are encoded by predatory colponemids, a sister group to the alveolates. These results reveal that the LAPs are much older than previously thought and pre-date not only the Apicomplexa but the Alveolata altogether.","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 6","pages":"230451"},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Greatwall-Endos-PP2A/B55^Twins network regulates translation and stability of maternal transcripts in the Drosophila oocyte-to-embryo transition. Greatwall-Endos-PP2A/B55Twins 网络调节果蝇卵母细胞向胚胎转化过程中母体转录本的翻译和稳定性。

IF 4.5 3区生物学

Open Biology Pub Date : 2024-06-01 Epub Date: 2024-06-19 DOI: 10.1098/rsob.240065

Hélène Rangone, Laura Bond, Timothy T Weil, David M Glover

{"title":"Greatwall-Endos-PP2A/B55Twins network regulates translation and stability of maternal transcripts in the Drosophila oocyte-to-embryo transition.","authors":"Hélène Rangone, Laura Bond, Timothy T Weil, David M Glover","doi":"10.1098/rsob.240065","DOIUrl":"10.1098/rsob.240065","url":null,"abstract":"The transition from oocyte to embryo requires translation of maternally provided transcripts that in Drosophila is activated by Pan Gu kinase to release a rapid succession of 13 mitotic cycles. Mitotic entry is promoted by several protein kinases that include Greatwall/Mastl, whose Endosulfine substrates antagonize Protein Phosphatase 2A (PP2A), facilitating mitotic Cyclin-dependent kinase 1/Cyclin B kinase activity. Here we show that hyperactive greatwallScant can not only be suppressed by mutants in its Endos substrate but also by mutants in Pan Gu kinase subunits. Conversely, mutants in me31B or trailer hitch, which encode a complex that represses hundreds of maternal mRNAs, enhance greatwallScant . Me31B and Trailer Hitch proteins, known substrates of Pan Gu kinase, copurify with Endos. This echoes findings that budding yeast Dhh1, orthologue of Me31B, associates with Igo1/2, orthologues of Endos and substrates of the Rim15, orthologue of Greatwall. endos-derived mutant embryos show reduced Me31B and elevated transcripts for the mitotic activators Cyclin B, Polo and Twine/Cdc25. Together, our findings demonstrate a previously unappreciated conservation of the Greatwall-Endosulfine pathway in regulating translational repressors and its interactions with the Pan Gu kinase pathway to regulate translation and/or stability of maternal mRNAs upon egg activation.","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 6","pages":"240065"},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141420296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MYH7 R453C induced cardiac remodelling via activating TGF-β/Smad2/3, ERK1/2 and Nox4/ROS/NF-κB signalling pathways. MYH7 R453C通过激活TGF-β/Smad2/3、ERK1/2和Nox4/ROS/NF-κB信号通路诱导心脏重塑。

IF 4.5 3区生物学

Open Biology Pub Date : 2024-06-01 Epub Date: 2024-06-12 DOI: 10.1098/rsob.230427

Lingyu Wang, Linquan Li, Dazhong Zhao, Hongming Yuan, Huanyu Zhang, Jiahuan Chen, Daxin Pang, Yi Lu, Hongsheng Ouyang

{"title":"MYH7 R453C induced cardiac remodelling via activating TGF-β/Smad2/3, ERK1/2 and Nox4/ROS/NF-κB signalling pathways.","authors":"Lingyu Wang, Linquan Li, Dazhong Zhao, Hongming Yuan, Huanyu Zhang, Jiahuan Chen, Daxin Pang, Yi Lu, Hongsheng Ouyang","doi":"10.1098/rsob.230427","DOIUrl":"10.1098/rsob.230427","url":null,"abstract":"Hypertrophic cardiomyopathy (HCM) is a monogenic cardiac disorder commonly induced by sarcomere gene mutations. However, the mechanism for HCM is not well defined. Here, we generated transgenic MYH7 R453C and MYH6 R453C piglets and found both developed typical cardiac hypertrophy. Unexpectedly, we found serious fibrosis and cardiomyocyte loss in the ventricular of MYH7 R453C, not MYH6 R453C piglets, similar to HCM patients. Then, RNA-seq analysis and western blotting identified the activation of ERK1/2 and PI3K-Akt pathways in MYH7 R453C. Moreover, we observed an increased expression of fetal genes and an excess of reactive oxygen species (ROS) in MYH7 R453C piglet models, which was produced by Nox4 and subsequently induced inflammatory response. Additionally, the phosphorylation levels of Smad2/3, ERK1/2 and NF-kB p65 proteins were elevated in cardiomyocytes with the MYH7 R453C mutation. Furthermore, epigallocatechin gallate, a natural bioactive compound, could be used as a drug to reduce cell death by adjusting significant downregulation of the protein expression of Bax and upregulated Bcl-2 levels in the H9C2 models with MYH7 R453C mutation. In conclusion, our study illustrated that TGF-β/Smad2/3, ERK1/2 and Nox4/ROS pathways have synergistic effects on cardiac remodelling and inflammation in MYH7 R453C mutation.","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 6","pages":"230427"},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural and functional insights into the C-terminal signal domain of the Bacteroidetes type-IX secretion system. 类杆菌 IX 型分泌系统 C 端信号域的结构和功能研究。

IF 4.5 3区生物学

Open Biology Pub Date : 2024-06-01 Epub Date: 2024-06-12 DOI: 10.1098/rsob.230448

Danuta Mizgalska, Arturo Rodríguez-Banqueri, Florian Veillard, Mirosław Książęk, Theodoros Goulas, Tibisay Guevara, Ulrich Eckhard, Jan Potempa, F Xavier Gomis-Rüth

{"title":"Structural and functional insights into the C-terminal signal domain of the Bacteroidetes type-IX secretion system.","authors":"Danuta Mizgalska, Arturo Rodríguez-Banqueri, Florian Veillard, Mirosław Książęk, Theodoros Goulas, Tibisay Guevara, Ulrich Eckhard, Jan Potempa, F Xavier Gomis-Rüth","doi":"10.1098/rsob.230448","DOIUrl":"10.1098/rsob.230448","url":null,"abstract":"Gram-negative bacteria from the Bacteroidota phylum possess a type-IX secretion system (T9SS) for protein secretion, which requires cargoes to have a C-terminal domain (CTD). Structurally analysed CTDs are from Porphyromonas gingivalis proteins RgpB, HBP35, PorU and PorZ, which share a compact immunoglobulin-like antiparallel 3+4 β-sandwich (β1-β7). This architecture is essential as a P. gingivalis strain with a single-point mutant of RgpB disrupting the interaction of the CTD with its preceding domain prevented secretion of the protein. Next, we identified the C-terminus ('motif C-t.') and the loop connecting strands β3 and β4 ('motif Lβ3β4') as conserved. We generated two strains with insertion and replacement mutants of PorU, as well as three strains with ablation and point mutants of RgpB, which revealed both motifs to be relevant for T9SS function. Furthermore, we determined the crystal structure of the CTD of mirolase, a cargo of the Tannerella forsythia T9SS, which shares the same general topology as in Porphyromonas CTDs. However, motif Lβ3β4 was not conserved. Consistently, P. gingivalis could not properly secrete a chimaeric protein with the CTD of peptidylarginine deiminase replaced with this foreign CTD. Thus, the incompatibility of the CTDs between these species prevents potential interference between their T9SSs.","PeriodicalId":19629,"journal":{"name":"Open Biology","volume":"14 6","pages":"230448"},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0